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Molecular Diagnostics

Tuft cell-like carcinomas: novel cancer subsets present in multiple organs sharing a unique gene expression signature

British Journal of Cancer volume 127, pages 1876–1885 (2022)Cite this article

Subjects

Abstract

Background

Tuft cells are chemosensory epithelial cells playing a role in innate immunity. Recent studies revealed cancers with a tuft cell-like gene expression signature in the thorax. We wondered whether this signature might also occur in extrathoracic cancers.

Methods

We examined mRNA expression of tuft cell markers (POU2F3, GFI1B, TRPM5, SOX9, CHAT, and AVIL) in 19 different types of cancers in multiple extrathoracic organs with The Cancer Genome Atlas (TCGA) (N = 6322). Four different extrathoracic cancers in our local archives (N = 909) were analysed by immunohistochemistry.

Results

Twenty-two (0.35%) extrathoracic tumours with co-expression of POU2F3 and other tuft cell markers were identified in various TCGA datasets. Twelve of the 22 “tuft cell-like tumours” shared poor differentiation and a gene expression pattern, including KIT, anti-apoptotic BCL2, and ionocyte-associated genes. In our archival cases, eleven (1.21%) tumours co-expressing POU2F3, KIT, and BCL2 on immunohistochemistry, i.e., were presumable tuft cell-like cancers. In three among five TCGA cohorts, the tuft cell-like cancer subsets expressed SLFN11, a promising biomarker of PARP inhibitor susceptibility.

Conclusions

Tuft cell-like carcinomas form distinct subsets in cancers of many organs. It appears warranted to investigate their shared gene expression signature as a predictive biomarker for novel therapeutic strategies.

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Fig. 1: mRNA expression of tuft cell-like tumours (TCGA, PanCancer Atlas).
Fig. 2: Hierarchical clustering of all 41 tuft cell-like tumours in the TCGA PanCancer Atlas (TCGA PanCancer Atlas).
Fig. 3: Histology and gene expression profile of tuft cell-like carcinomas (TCGA PanCancer Atlas).
Fig. 4: Histological and immunohistochemical features of tuft cell-like tumours of extrathoracic organs from our local archives.
Fig. 5
Fig. 6: Expression of SLFN11 in tuft cell-like tumours (TCGA, PanCancer Atlas) and the current model of tuft cell-like malignancy.

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Data availability

The data on TCGA and PanCancer Atlas that support the findings of this study are available in cBioPortal (http://www.cbioportal.org/).

References

  1. von Moltke J, Ji M, Liang HE, Locksley RM. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature. 2016;529:221–5.

    Article  Google Scholar 

  2. Howitt MR, Lavoie S, Michaud M, Blum AM, Tran SV, Weinstock JV, et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science. 2016;351:1329–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardalhon V, et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature. 2016;529:226–30.

    Article  CAS  PubMed  Google Scholar 

  4. Schneider C, O’Leary CE, Locksley RM. Regulation of immune responses by tuft cells. Nat Rev Immunol. 2019;19:584–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Huang YH, Klingbeil O, He XY, Wu XS, Arun G, Lu B, et al. POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes Dev. 2018;32:915–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schütz B, Ruppert AL, Strobel O, Lazarus M, Urade Y, Büchler MW, et al. Distribution pattern and molecular signature of cholinergic tuft cells in human gastro-intestinal and pancreatic-biliary tract. Sci Rep. 2019;9:17466.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bornstein C, Nevo S, Giladi A, Kadouri N, Pouzolles M, Gerbe F, et al. Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells. Nature. 2018;559:622–6.

    Article  CAS  PubMed  Google Scholar 

  8. Miller CN, Proekt I, von Moltke J, Wells KL, Rajpurkar AR, Wang H, et al. Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. Nature. 2018;559:627–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nevo S, Kadouri N, Abramson J. Tuft cells: from the mucosa to the thymus. Immunol Lett. 2019;210:1–9.

    Article  CAS  PubMed  Google Scholar 

  10. Goto N, Fukuda A, Yamaga Y, Yoshikawa T, Maruno T, Maekawa H, et al. Lineage tracing and targeting of IL17RB+ tuft cell-like human colorectal cancer stem cells. Proc Natl Acad Sci USA. 2019;116:12996–3005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nakanishi Y, Seno H, Fukuoka A, Ueo T, Yamaga Y, Maruno T, et al. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat Genet. 2013;45:98–103.

    Article  CAS  PubMed  Google Scholar 

  12. DelGiorno KE, Chung CY, Vavinskaya V, Maurer HC, Novak SW, Lytle NK, et al. Tuft cells inhibit pancreatic tumorigenesis in mice by producing prostaglandin D2. Gastroenterology. 2020;159:1866.e8–81.e8.

    Article  Google Scholar 

  13. Yamashita J, Ohmoto M, Yamaguchi T, Matsumoto I, Hirota J. Skn-1a/Pou2f3 functions as a master regulator to generate Trpm5-expressing chemosensory cells in mice. PLoS ONE. 2017;12:e0189340.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Yamada Y, Simon-Keller K, Belharazem-Vitacolonnna D, Bohnenberger H, Kriegsmann M, Kriegsmann K, et al. A tuft cell-like signature is highly prevalent in thymic squamous cell carcinoma and delineates new molecular subsets among the major lung cancer histotypes. J Thorac Oncol. 2021;16:1003–16.

    Article  CAS  PubMed  Google Scholar 

  15. Baine MK, Hsieh MS, Lai WV, Egger JV, Jungbluth AA, Daneshbod Y, et al. SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization. J Thorac Oncol. 2020;15:1823–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rudin CM, Poirier JT, Byers LA, Dive C, Dowlati A, George J, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019;19:289–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gay CM, Stewart CA, Park EM, Diao L, Groves SM, Heeke S, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39:346.e7–60.e7.

    Article  Google Scholar 

  18. Yoshino T, Pentheroudakis G, Mishima S, Overman MJ, Yeh KH, Baba E, et al. JSCO-ESMO-ASCO-JSMO-TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions. Ann Oncol. 2020;31:861–72.

    Article  CAS  PubMed  Google Scholar 

  19. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Article  PubMed  Google Scholar 

  20. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    Article  PubMed  PubMed Central  Google Scholar 

  21. George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524:47–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, et al. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun. 2018;9:1048.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Montoro DT, Haber AL, Biton M, Vinarsky V, Lin B, Birket SE, et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature. 2018;560:319–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Plasschaert LW, Žilionis R, Choo-Wing R, Savova V, Knehr J, Roma G, et al. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature. 2018;560:377–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Coleman N, Zhang B, Byers LA, Yap TA. The role of Schlafen 11 (SLFN11) as a predictive biomarker for targeting the DNA damage response. Br J Cancer. 2021;124:857–9.

    Article  CAS  PubMed  Google Scholar 

  26. Winkler C, Armenia J, Jones GN, Tobalina L, Sale MJ, Petreus T, et al. SLFN11 informs on standard of care and novel treatments in a wide range of cancer models. Br J Cancer. 2021;124:951–62.

    Article  CAS  PubMed  Google Scholar 

  27. Rathkey D, Khanal M, Murai J, Zhang J, Sengupta M, Jiang Q, et al. Sensitivity of mesothelioma cells to PARP inhibitors is not dependent on BAP1 but is enhanced by temozolomide in cells with high-Schlafen 11 and low-O6-methylguanine-DNA methyltransferase expression. J Thorac Oncol. 2020;15:843–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lok BH, Gardner EE, Schneeberger VE, Ni A, Desmeules P, Rekhtman N, et al. PARP inhibitor activity correlates with SLFN11 expression and demonstrates synergy with temozolomide in small cell lung cancer. Clin Cancer Res. 2017;23:523–35.

    Article  CAS  PubMed  Google Scholar 

  29. Pietanza MC, Waqar SN, Krug LM, Dowlati A, Hann CL, Chiappori A, et al. Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer. J Clin Oncol. 2018;36:2386–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Polley E, Kunkel M, Evans D, Silvers T, Delosh R, Laudeman J, et al. Small cell lung cancer screen of oncology drugs, investigational agents, and gene and microRNA expression. J Natl Cancer Inst. 2016;108:djw122.

  31. Bautista JL, Cramer NT, Miller CN, Chavez J, Berrios DI, Byrnes LE, et al. Single-cell transcriptional profiling of human thymic stroma uncovers novel cellular heterogeneity in the thymic medulla. Nat Commun. 2021;12:1096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huang N, Pérez P, Kato T, Mikami Y, Okuda K, Gilmore RC, et al. SARS-CoV-2 infection of the oral cavity and saliva. Nat Med. 2021;27:892–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Skala SL, Wang X, Zhang Y, Mannan R, Wang L, Narayanan SP, et al. Next-generation RNA sequencing-based biomarker characterization of chromophobe renal cell carcinoma and related oncocytic neoplasms. Eur Urol. 2020;78:63–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Goldfarbmuren KC, Jackson ND, Sajuthi SP, Dyjack N, Li KS, Rios CL, et al. Dissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium. Nat Commun. 2020;11:2485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chan JM, Quintanal-Villalonga Á, Gao VR, Xie Y, Allaj V, Chaudhary O, et al. Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer. Cancer Cell. 2021;39:1479–96. e18

    Article  CAS  PubMed  Google Scholar 

  36. Pozo K, Kollipara RK, Kelenis DP, Rodarte KE, Ullrich MS, Zhang X, et al. ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer. iScience. 2021;24:102953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Radovich M, Pickering CR, Felau I, Ha G, Zhang H, Jo H, et al. The integrated genomic landscape of thymic epithelial tumors. Cancer Cell. 2018;33:244.e10–58.e10.

    Article  Google Scholar 

  38. WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon: International Agency for Research on Cancer; 2019.

  39. Murai J, Thomas A, Miettinen M, Pommier Y. Schlafen 11 (SLFN11), a restriction factor for replicative stress induced by DNA-targeting anti-cancer therapies. Pharm Ther. 2019;201:94–102.

    Article  CAS  Google Scholar 

  40. Zhu Q, Zhan P, Zhang X, Lv T, Song Y. Clinicopathologic characteristics of patients with ROS1 fusion gene in non-small cell lung cancer: a meta-analysis. Transl Lung Cancer Res. 2015;4:300–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wu XS, He XY, Ipsaro JJ, Huang YH, Preall JB, Ng D, et al. OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage. Nature. 2022;607:169–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Baine MK, Febres-Aldana CA, Chang JC, Jungbluth AA, Sethi S, Antonescu CR, et al. POU2F3 in SCLC: clinicopathologic and genomic analysis with a focus on its diagnostic utility in neuroendocrine-low SCLC. J Thorac Oncol. 2022. https://doi.org/10.1016/j.jtho.2022.06.004.

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Funding

Y.Y. is currently receiving a grant, JSPS KAKENHI Grant Number JP21K06902.

Author information

Authors and Affiliations

  1. Institute of Pathology, University Medical Centre Mannheim and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Yosuke Yamada & Alexander Marx

  2. Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan

    Yosuke Yamada, Masakazu Fujimoto, Sachiko Minamiguchi & Hironori Haga

  3. Institute of Pathology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany

    Hanibal Bohnenberger & Philipp Ströbel

  4. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    Mark Kriegsmann & Peter Sinn

  5. German Center for Lung Cancer Research (DZL), Heidelberg, Germany

    Mark Kriegsmann

  6. Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany

    Katharina Kriegsmann

  7. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Norihiro Goto, Yuki Nakanishi & Hiroshi Seno

  8. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Yoshitsugu Chigusa

  9. Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Ronald Simon & Guido Sauter

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  1. Yosuke Yamada
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Contributions

Experimental design and idea: YY, HB, AM. Data mining and statistical analysis: YY. Tissue (including tissue microarrays), clinical and molecular data acquisition: HB, MK, KK, PS, NG, YN, HS, HC, RS, GS. Pathology analysis: YY, HB, MK, KK, PS, MF, SM, HH, PS, AM. Manuscript writing: YY, HB, PS, AM. Correction and approval of manuscript: all authors.

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Correspondence to Yosuke Yamada.

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The authors declare no competing interests.

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The study was approved by the local Ethics Committee II, University of Heidelberg, approval no. 2017-806R-MA and the ethical committee of Kyoto University Hospital.

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Yamada, Y., Bohnenberger, H., Kriegsmann, M. et al. Tuft cell-like carcinomas: novel cancer subsets present in multiple organs sharing a unique gene expression signature. Br J Cancer 127, 1876–1885 (2022). https://doi.org/10.1038/s41416-022-01957-6

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